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Background: Acute myocardial injury after noncardiac surgery, which is most often symptomatically silent, is associated with increased mortality and morbidity. However, it is not known if routine postoperative troponin testing will affect patient outcomes., Methods: We assembled a cohort of patients who underwent carotid endarterectomy or abdominal aortic aneurysm repair in Ontario, Canada, from 2010 to 2017. Hospitals were categorized into high, medium, and low troponin testing intensity based on the proportion of patients who received postoperative troponin testing. Cox proportional hazards modeling was used to assess the association between hospital-specific testing intensity and 30-day and 1-year major adverse cardiovascular events (MACEs) while adjusting for patient-, surgery-, and hospital-level factors., Results: The cohort consisted of 18,467 patients from 17 hospitals. Mean age was 72 years, and 74.0% were men. Rates of postoperative troponin testing were 77.5%, 35.8%, and 21.6% in the high-, medium-, and low-testing intensity hospitals, respectively. At 30 days, 5.3%, 5.3%, and 6.5% of patients in high-, medium-, and low-testing intensity hospitals experienced MACE, respectively. Higher troponin testing rate was associated with lower adjusted hazard ratios (HRs) for MACE at 30 days (0.94; 95% confidence interval [CI], 0.89-0.98) and at 1 year (0.97; 95% CI, 0.94-0.99) for each 10% increase in hospital troponin rate. Hospitals with high-testing intensity had higher rates of postoperative cardiology referrals, cardiovascular testing, and rates of new cardiovascular prescriptions., Conclusions: Patients undergoing vascular surgery at hospitals with higher postoperative troponin testing intensity experienced fewer adverse outcomes than patients who had surgery at hospitals with lower testing intensity., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

Background: International practice guidelines make different recommendations for postoperative troponin testing to detect perioperative myocardial infarction and myocardial injury after noncardiac surgery. To gain insights into current testing patterns, we evaluated predictors of routine troponin testing after three commonly performed major noncardiac surgeries., Methods: We conducted a population-based historical cohort study of adults having major orthopedic, colorectal, or vascular surgery in Ontario, Canada from 1 January 2010 to 31 December 2017. We used hierarchical logistic regression modelling to assess the association of patient, surgery, and hospital factors with postoperative troponin testing, while accounting for clustering at the hospital level. We characterized hospital-level variation by the intraclass correlation coefficient (ICC), which was adjusted for various characteristics., Results: The cohort included 176,454 eligible patients. Hospital-specific adjusted testing rates ranged from 0-20.1% for orthopedic surgery, 0-43.8% for colorectal surgery, and 19.6-88.0% for vascular surgery. Older age, urgent surgery status, and surgery duration were consistently associated with higher rates of testing for all three surgeries. Higher Revised Cardiac Risk Index scores were associated with higher odds of testing for orthopedic and colorectal surgery, but not for vascular surgery. Even after adjustment, the ICCs were 9.2%, 7.4%, and 24.1% for orthopedic, general, and vascular surgery, respectively., Conclusions: Troponin testing varied substantially across hospitals for selected major noncardiac surgery procedures even after accounting for differences in patient-level cardiac risk factors. Our observations lend support to a more standardized approach for troponin testing after noncardiac surgery., (© 2022. Canadian Anesthesiologists' Society.)

Background: Renin-angiotensin-aldosterone system inhibitors (RAASIs) are recommended for most patients with coronary artery disease (CAD). However, there is debate across guidelines as to which patients with CAD benefit the most from these agents. This study investigated the association between RAASIs and cardiovascular outcomes and acute kidney injury in a contemporary cohort of patients with CAD., Methods: Patients ≥65 years of age with CAD alive on April 1, 2012 in Ontario, Canada were included. Outcomes included major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction (MI), unstable angina, stroke, or coronary revascularization), and acute kidney injury (AKI) hospitalizations at 4 years. Inverse probability of treatment-weighted Cox proportional hazards regression models was used to compare the rates of each outcome in patients treated with and without RAASIs (angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers)., Results: There were 165,058 patients with CAD identified (mean age 75 years, 65.5% male, 64.7% prescribed RAASIs). After inverse-probability weighting, treatment with RAASIs was associated with a lower rate of MACE compared with treatment without RAASIs (17.6% vs 18.2%, hazard ratio [HR]: 0.96, 95% CI: 0.93-0.99, respectively). However, treatment with RAASIs was associated with a higher rate of AKI compared with treatment without RAASIs (1.7% vs 1.5%, HR: 1.14, 95% CI: 1.02-1.29, respectively). The reduction in MACE was greater in patients with prior MI (HR: 0.87, 95% CI: 0.82-0.92) compared with patients without prior MI (HR: 1.00, 95% CI: 0.97-1.04, interaction p < 0.01). The increase in AKI was lower in patients with prior MI (HR: 0.82, 95% CI: 0.66-1.00) compared with patients without prior MI (HR: 1.37, 95% CI: 1.19-1.57, interaction p < 0.01)., Conclusions: This study supports the continued use of RAASIs in patients with CAD, although the benefit appears smaller in magnitude than observed in prior trials. High-risk patients, particularly those with prior MI, appear to benefit the most from RAASIs., (© 2021 Pharmacotherapy Publications, Inc.)

Aims: The economic value of transcatheter aortic valve replacement (TAVR) in low surgical risk patients with severe, symptomatic aortic stenosis is not known. Our objective was to determine the cost-effectiveness of balloon-expandable TAVR and self-expandable TAVR relative to surgical aortic valve replacement (SAVR) in low-risk patients., Methods and Results: A fully probabilistic Markov cohort model was constructed to estimate differences in costs and effectiveness [quality-adjusted life years (QALYs)] over the patient's life-time time from the third-party payer's perspective. Clinical outcomes modelled were alive/well (no complications), permanent stroke, ≥moderate paravalvular leak, new pacemaker, rehospitalization, and death. A network meta-analysis of the PARTNER 3 and Evolut Low Risk trial was performed to compare balloon-expandable TAVR, self-expandable TAVR, and SAVR for the efficacy inputs. Incremental-cost effectiveness ratios (ICER) were calculated. The total life-time costs in the balloon-expandable TAVR, self-expandable-TAVR, and SAVR arms were $37  330 ± 4724, $39 660 ± 4862, and $34 583 ± 6731, respectively, and total life-time QALYs gained were 9.15 ± 3.23, 9.13 ± 3.23, and 9.05 ± 3.20, respectively. The ICERs for balloon-expandable TAVR and self-expandable TAVR against SAVR were $27 196/QALY and $59 641/QALY, respectively. Balloon-expandable TAVR was less costly and more effective than self-expandable TAVR. There was substantial uncertainty, with 53% and 58% of model iterations showing balloon-expandable TAVR to be the preferred option at willingness-to-pay thresholds of $50 000/QALY and $100  000/QALY, respectively., Conclusion: Compared with SAVR, TAVR, particularly with balloon-expandable prostheses may be a cost-effective option for patients with severe aortic stenosis at low surgical risk., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: In 2017, the Canadian Cardiovascular Society (CCS) published guidelines recommending postoperative troponin surveillance in higher-risk patients having major noncardiac surgery. The objective of this study was to evaluate the proportion of major noncardiac surgery patients that would meet recommendations for troponin testing and to assess the rates of troponin testing before guideline adoption., Methods: We conducted a retrospective observational study of patients age 40 to 105 undergoing a subset of major noncardiac surgeries that included orthopedics, gynecology, general, urology, vascular, and thoracic surgeries in Ontario, Canada from January 1, 2010 to December 31, 2017. The primary outcomes were the proportion of patients recommended for testing based on the guidelines and rates of troponin testing within 2 days of surgery., Results: We identified 257,704 patients who underwent noncardiac surgery. Mean age was 66.4 ± 11.9 years, and 12.4% underwent urgent surgery. Applying the CCS guidelines, 71.2% of elective surgery patients and 81.0% of urgent surgery patients would have met recommendations for postoperative troponin screening, whereas 10.8% and 27.1% received postoperative troponin testing, respectively. Most elective surgery patients met recommendations for testing based on the age criterion (54.9%), followed by diabetes (24.6%) and high-risk surgery (22.7%) criteria. Troponin testing varied substantially by types of surgery: highest for open abdominal aortic aneurisms and lowest for hysterectomies., Conclusions: Based on the CCS guidelines, most patients undergoing the subset of surgeries assessed would have met recommendations for routine troponin testing. In contrast, routine troponin testing before guideline adoption was done infrequently in Ontario, with substantial variations based on the surgery type., (© 2021 The Authors.)

Aim: Intensified haemodialysis is associated with regression of left ventricular (LV) mass. Compared to LV ejection fraction, LV strain allows more direct assessment of LV function. We sought to assess the impact of in-centre nocturnal haemodialysis (INHD) on global LV strain (radial, circumferential, and longitudinal) and torsion by cardiac MRI (CMR)., Methods: In this prospective, two-centre cohort study, 37 participants on conventional haemodialysis (CHD, 3-4 h/session for three sessions/week) converted to INHD (7-8 h/session for three sessions/week) and 30 participants continued CHD. Participants underwent CMR using a standardized protocol and had biomarker measurements at baseline and 52 weeks., Results: Among the 55 participants (mean age 55; 40% women) with complete CMR data, those who converted to INHD had a significant improvement in their global circumferential strain (GCS, P = 0.025), while those continuing CHD did not have any significant changes in LV strain. When the two groups were compared, there was significant improvement in torsion. LV strains were significantly correlated with each other, but not with troponin I, C-reactive protein, or brain natriuretic protein (NT-proBNP), except for global longitudinal strain (GLS) with troponin I (P = 0.001) and NT-proBNP (P = 0.038)., Conclusion: Conversion to INHD was associated with significant improvement in GCS over one year of study, although comparisons with the CHD group were not significant. There was also a significant decrease in torsion in the INHD group compared with CHD. Improvement in LV regional function would support the notion that INHD has favourable effects on both LV structure and function., (© 2018 Asian Pacific Society of Nephrology.)

Discovery of common pathways that mediate both pancreatic β-cell function and end-organ function offers the opportunity to develop therapies that modulate glucose homeostasis and separately slow the development of diabetes complications. Here, we investigated the in vitro and in vivo effects of pharmacological agonism of the prostaglandin I2 (IP) receptor in pancreatic β-cells and in glomerular podocytes. The IP receptor agonist MRE-269 increased intracellular 3',5'-cyclic adenosine monophosphate (cAMP), augmented glucose-stimulated insulin secretion (GSIS), and increased viability in MIN6 β-cells. Its prodrug form, selexipag, augmented GSIS and preserved islet β-cell mass in diabetic mice. Determining that this preservation of β-cell function is mediated through cAMP/protein kinase A (PKA)/nephrin-dependent pathways, we found that PKA inhibition, nephrin knockdown, or targeted mutation of phosphorylated nephrin tyrosine residues 1176 and 1193 abrogated the actions of MRE-269 in MIN6 cells. Because nephrin is important to glomerular permselectivity, we next set out to determine whether IP receptor agonism similarly affects nephrin phosphorylation in podocytes. Expression of the IP receptor in podocytes was confirmed in cultured cells by immunoblotting and quantitative real-time PCR and in mouse kidneys by immunogold electron microscopy, and its agonism 1) increased cAMP, 2) activated PKA, 3) phosphorylated nephrin, and 4) attenuated albumin transcytosis. Finally, treatment of diabetic endothelial nitric oxide synthase knockout mice with selexipag augmented renal nephrin phosphorylation and attenuated albuminuria development independently of glucose change. Collectively, these observations describe a pharmacological strategy that posttranslationally modifies nephrin and the effects of this strategy in the pancreas and in the kidney., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Obesity is associated with inflammation and immune cell recruitment to adipose tissue, muscle and intima of atherosclerotic blood vessels. Obesity and hyperlipidemia are also associated with tissue insulin resistance and can compromise insulin delivery to muscle. The muscle/fat microvascular endothelium mediates insulin delivery and facilitates monocyte transmigration, yet its contribution to the consequences of hyperlipidemia is poorly understood. Using primary endothelial cells from human adipose tissue microvasculature (HAMEC), we investigated the effects of physiological levels of fatty acids on endothelial inflammation and function. Expression of cytokines and adhesion molecules was measured by RT-qPCR. Signaling pathways were evaluated by pharmacological manipulation and immunoblotting. Surface expression of adhesion molecules was determined by immunohistochemistry. THP1 monocyte interaction with HAMEC was measured by cell adhesion and migration across transwells. Insulin transcytosis was measured by total internal reflection fluorescence microscopy. Palmitate, but not palmitoleate, elevated the expression of IL-6, IL-8, TLR2 (Toll-like receptor 2), and intercellular adhesion molecule 1 (ICAM-1). HAMEC had markedly low fatty acid uptake and oxidation, and CD36 inhibition did not reverse the palmitate-induced expression of adhesion molecules, suggesting that inflammation did not arise from palmitate uptake/metabolism. Instead, inhibition of TLR4 to NF-κB signaling blunted palmitate-induced ICAM-1 expression. Importantly, palmitate-induced surface expression of ICAM-1 promoted monocyte binding and transmigration. Conversely, palmitate reduced insulin transcytosis, an effect reversed by TLR4 inhibition. In summary, palmitate activates inflammatory pathways in primary microvascular endothelial cells, impairing insulin transport and increasing monocyte transmigration. This behavior may contribute in vivo to reduced tissue insulin action and enhanced tissue infiltration by immune cells., (Copyright © 2015 the American Physiological Society.)

Transport of insulin across the microvasculature is necessary to reach its target organs (e.g., adipose and muscle tissues) and is rate limiting in insulin action. Morphological evidence suggests that insulin enters endothelial cells of the microvasculature, and studies with large vessel-derived endothelial cells show insulin uptake; however, little is known about the actual transcytosis of insulin and how this occurs in the relevant microvascular endothelial cells. We report an approach to study insulin transcytosis across individual, primary human adipose microvascular endothelial cells (HAMECs), involving insulin uptake followed by vesicle-mediated exocytosis visualized by total internal reflection fluorescence microscopy. In this setting, fluorophore-conjugated insulin exocytosis depended on its initial binding and uptake, which was saturable and much greater than in muscle cells. Unlike its degradation within muscle cells, insulin was stable within HAMECs and escaped lysosomal colocalization. Insulin transcytosis required dynamin but was unaffected by caveolin-1 knockdown or cholesterol depletion. Instead, insulin transcytosis was significantly inhibited by the clathrin-mediated endocytosis inhibitor Pitstop 2 or siRNA-mediated clathrin depletion. Accordingly, insulin internalized for 1 min in HAMECs colocalized with clathrin far more than with caveolin-1. This study constitutes the first evidence of vesicle-mediated insulin transcytosis and highlights that its initial uptake is clathrin dependent and caveolae independent., (© 2015 Azizi et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)